Mushrooms and their extracts have been used for centuries throughout numerous Asian societies as an alternative therapy for cancer. Preliminary reports suggest that mushroom extracts can directly inhibit tumor cell invasion and metastasis through the regulation of proteases. Ganoderma Lucidum (Reishi) contain a number of bioactive compounds including triterpenes which can down-regulate MMP-9, a member of the matrix metalloprotease (MMP) family of genes. Expression and activity of MMPs are a rate-limiting step in the control of tumor cell invasion and metastasis. Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. While prostate cancer will respond to androgen deprivation, most deaths from prostate cancer are caused by metastases that resist conventional androgen-deprivation therapy. In the past 10 years several chemotherapeutic agents have demonstrated activity in up to 70% of patients. However, these regimens have not as yet been proven to improve survival. Clearly, there remains a need to identify novel therapeutic agents that will impact upon survival of this patient population. We hypothesize that the ability of Reishi to regulate MMP expression and to inhibit growth and metastasis of androgen-resistant and chemotherapy-resistant prostate cancer depends upon the triterpene content of the mushroom extract. To test this hypothesis, we will assess the ability of these extracts to inhibit mRNA and protein expression of matrix metalloproteinases (MMP) of the androgen-resistant and chemoresistant cell lines. We will then study their inhibition of enzyme activity as well as cellular motility and invasion. Finally, the cell lines will be injected into prostate and femurs of athymic nude mice and then treated with the ganoderma extracts with different levels of triterpenes. Serum and tumors will be harvested and analyzed for changes in tumor growth and metastasis as well as for changes in MMP expression. Tumor response will also be correlated with serum triterpene levels. We believe these experiments will allow us to determine whether triterpene concentration affects the ability of mushroom extracts to inhibit protease expression as well as the growth and metastasis of prostate cancer. These results should provide preliminary evidence to determine which G. Lucidum strains should be evaluated in Phase I human clinical trials.